The present invention relates to pharmaceutical compositions containing irbesartan, preferably in the form of a tablet. The present invention also relates to tablets prepared from these compositions.
Irbesartan, 2-n-butyl-4-spirocyclopentane-1-[(2xe2x80x2-(tetrazol-5-yl)biphenyl-4-yl)methyl]-2-imidazolin-5-one, is a potent, long-acting angiotensin II receptor antagonist which is particularly useful in the treatment of cardiovascular ailments such as hypertension and heart failure. Irbesartan has the following structure: 
and is described in Bernhart et al., U.S. Pat. No. 5,270,317, incorporated herein by reference. Preferred pharmaceutical compositions of this drug contain, as active ingredient(s), irbesartan alone or in combination with a diuretic such as hydrochlorothiazide.
Irbesartan may be administered in dosages containing a substantial quantity of the active agent (e.g., 75-300 mg). Certain physical properties of the drug present a challenge in developing formulations suitable for preparing a tablet having both a substantial quantity of active agent and a small enough tablet mass to allow ease of swallowing.
Irbesartan is, for example, a fluffy material, with relatively low bulk and tap densities. These properties make it difficult to formulate a large amount of the drug into a small tablet with uniformity of weight, hardness, and other desirable tablet properties. In addition, irbesartan has certain undesirable flow characteristics, for example, is sticky and can adhere to surfaces such as tablet punch faces and dies, causing problems in tableting, especially on a high speed tablet press. The low aqueous solubility of irbesartan also presents a challenge, since, to keep the tablet mass small, only limited amounts of excipients may be added to facilitate wetting, disintegration, and ultimately, rapid and complete drug release. The addition of a diuretic such as hydrochlorothiazide, which is also a fluffy material exhibiting poor flow and low aqueous solubility, can further contribute to tableting problems.
Thus, there is a need in the art for pharmaceutical compositions containing irbesartan, alone or in combination with a diuretic, which have good properties for tablet formation, and yet which contain a low mass of excipients so that small, easily swallowed tablets with a high content of active agent may be prepared.
The present invention provides pharmaceutical compositions containing irbesartan, alone or in combination with a diuretic, which (1) have a minimal mass of added excipients, thereby allowing preparation of small, easily swallowed tablets which enhance patient acceptance and compliance, and yet which (2) have excellent properties for tablet formation, and (3) provide tablets with excellent wetting, disintegration, and ultimately, rapid and complete drug release properties.
In particular, the present invention provides pharmaceutical compositions, especially suitable for forming tablets, comprising from about 20 to about 70% by weight irbesartan or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients, wherein a tablet formed from aid composition has a dissolution performance such that about 80% or greater, preferably 85% or greater, of the irbesartan or salts thereof contained in said tablet dissolve within 30 minutes. The present compositions optionally also comprise from about 2 to about 33% diuretic, wherein the combined amount of irbesartan and diuretic does not exceed about 85%.
Preferred compositions containing irbesartan comprise, based on a total of 100% by weight: (a) from about 20 to about 70% (preferably, about 50%) irbesartan, (b) from about 1 to about 70% diluent, (c) from about 2 to about 20% binder, (d) from about 1 to about 10% disintegrant, (e) from about 0.1 to about 5% antiadherent, and (f) from about 0.2 to about 5% lubricant, and, optionally (g) from about 0.2 to about 6% surfactant, and/or (h) up to about 2% (preferably, from about 0.1 to about 1%) coloring agent.
Preferred compositions containing irbesartan and diuretic comprise, based on a total of 100% by weight: (a) from about 20 to about 70% (preferably, about 50%) irbesartan, (b) from about 2 to about 33% diuretic, wherein the combined loading of (a) and (b) does not exceed about 85%, (c) from about 1 to about 70% diluent, (d) from about 2 to about 20% binder, (e) from about 1 to about 10% disintegrant, (f) from about 0.1 to about 5% antiadherent, and (g) from about 0.2 to about 5% lubricant, and, optionally, (h) up to about 2% (preferably, from about 0.1 to about 1%) coloring agent.
The present compositions may contain up to about 70% w/w irbesartan, or up to about 85% w/w irbesartan and diuretic, and yet can be employed in the reproducible manufacture of tablets on a large scale. The present compositions can, for example, be compressed on high speed tableting equipment (especially, a high speed tablet press) to form tablets which are uniform in both weight and content and which exhibit desirable physical properties, including elegant appearance, low friability, and fast disintegration time. Tablets prepared from the present compositions are capable of releasing the active component(s), by dissolution, in a fast and reproducible manner.
Unless otherwise indicated, mention of irbesartan herein also includes pharmaceutically acceptable salts thereof.
The present invention is described in further detail as follows. The components employed in the compositions of the present invention should be pharmaceutically acceptable, particularly as described in the National Formulary (NF) or United States Pharmacopeia (USP).
The xe2x80x9cdissolution performancexe2x80x9d of a tablet, as used herein with respect to irbesartan, refers to the weight % of irbesaftan, based on the total weight of irbesartan contained in the tablet, which dissolves within 30 minutes under the following conditions: using a tablet having a total weight of from 150 to 600 mg and a USP Apparatus 2, placing the tablet in 1000 mL of 0.1 N hydrochloric acid at 37xc2x0 C., with a paddle speed of 50 rpm, and measuring the amount of irbesartan dissolved (especially, using UV at 244 nm or, when hydrochlorothiazide is also present, using HPLC, wavelength 272 nm) at 30 minutes. (If desired, the progress of dissolution may also be monitored at various time points.)
The xe2x80x9cdissolution performancexe2x80x9d of a tablet, as used herein with respect to a diuretic (preferably, hydrochlorothiazide), refers to the weight % of diuretic, based on the total weight of diuretic contained in the tablet, which dissolves within 30 minutes under the conditions described above for irbesartan dissolution. The dissolution performance for the diuretic preferably meets the USP dissolution specification for the diuretic (for hydrochlorothiazide, greater than 60% dissolution at 30 minutes). The dissolution performance of a tablet containing hydrochlorothiazide is most preferably such that about 90% or greater of the hydrochlorothiazide is dissolved at 30 minutes.
The xe2x80x9cdiureticxe2x80x9d employed in a composition of the present invention may be any suitable diuretic, or combination of two or more diuretics, such as hydrochlorothiazide, bendroflumethiazide, benzthiazide, chlorothiazide, chlorthalidone, cyclothiazide, hydroflumethiazide, methyclothiazide, metolazone, polythiazide, quinethazone, and trichlormethiazide. Preferably, the diuretic is hydrochlorothiazide.
The xe2x80x9cdiluentxe2x80x9d employed in a composition of the present invention may be one or more compounds which are capable of providing bulk to obtain a desired tablet mass. It is desirable to employ the diluent in an amount at the lower end of the weight range for the diluent. Preferred diluents are inorganic phosphates such as dibasic calcium phosphate; sugars such as lactose hydrous or lactose anhydrous; and cellulose or cellulose derivatives such as microcrystalline cellulose.
The xe2x80x9cbinderxe2x80x9d employed in a composition of the present invention may be one or more compounds which are capable of facilitating granulation of the irbesartan and/or diuretic into larger, denser, and/or more free-flowing particles. Preferred binders are alginic acid (most preferably employed in the range of 2-5% by weight) or sodium alginate (most preferably employed in the range of 2-3% by weight); cellulose or cellulose derivatives such as carboxymethylcellulose sodium (most preferably employed in the range of 2-6% by weight), ethylcellulose (most preferably employed in the range of 2-3% by weight), hydroxyethyl cellulose (most preferably employed in the range of 2-5% by weight), hydroxypropyl cellulose (most preferably employed in the range of 2-6% by weight), hydroxypropyl methylcellulose (most preferably employed in the range of 2-5% by weight), or methylcellulose (most preferably employed in the range of 2-6% by weight); gelatin (most preferably employed in the range of 2-10% by weight); povidone (polyvinylpyrrolidone, i.e., 1-ethenyl-2-pyrrolidinone homopolymer) (e.g., povidone K-30) (most preferably employed in the range of 2-20% by weight); or starch (most preferably employed in the range of 5-20% by weight) or pregelatinized starch (most preferably employed in the range of 2-20, such as 5-20% by weight).
The xe2x80x9cdisintegrantxe2x80x9d employed in a composition of the present invention may be one or more compounds which are capable of facilitating the break up of a tablet prepared from the composition when placed in contact with an aqueous medium. Preferred disintegrants are alginic acid (most preferably employed in the range of 2-5% by weight) or sodium alginate (most preferably employed in the range of 2.5-10% by weight); cellulose or cellulose derivatives such as carboximethylcellulose sodium (most preferably employed in the range of 2-6% by weight), microcrystalline cellulose (most preferably employed in the range of 5xe2x88x92-15% by weight), powdered cellulose (most preferably employed in the range of 5-15% by weight), or croscarmellose sodium (cross-linked polymer of carboxymethylcellulose sodium) (most preferably employed in the range of 2-5% by weight); crospovidone (cross-linked homopolymer of N-vinyl-2-pyrrolidinone, i.e., cross-linked 1-ethenyl-2-pyrrolidinone) (most preferably employed in the range of 2-5% by weight); pregelatinized starch (most preferably employed in the range of 5-10% by weight), sodium starch glycolate (most preferably employed in the range of 2-8% by weight), or starch (most preferably employed in the range of 3-15% by weight).
The xe2x80x9cantiadherentxe2x80x9d employed in a composition of the present invention may be one or more compounds which are capable of reducing the stickiness of the formulation, for example, preventing adherence to metal surfaces. Preferred antiadherents are silicon-containing compounds such as silicon dioxide (most preferably employed in the range of 0.25-5% (such as 0.5-2 or 2.5 to 3.0%) by weight), magnesium trisilicate (most preferably employed in the range of 0.5-2% by weight), or talc (most preferably employed in the range of 1-5% by weight).
The xe2x80x9clubricantxe2x80x9d employed in a composition of the present invention may be one or more compounds which are capable of preventing tableting problems, such as those relating to the release of a tablet prepared from the composition from the apparatus on which it is formed, for example, preventing adherence to the face of the upper punch (picking) or lower punch (sticking) of a tableting apparatus. Preferred lubricants are fatty acids or fatty acid derivatives such as calcium stearate (most preferably employed in the range of 0.5-2% by weight), glyceryl monostearate (most preferably employed in the range of 0.5-2% by weight), glyceryl palmitostearate (most preferably employed in the range of 0.5-2% by weight), magnesium stearate (most preferably employed in the range of 0.2-2% by weight), sodium lauryl sulfate (most preferably employed in the range of 1-2% by weight), sodium stearyl fumarate (most preferably employed in the range of 0.5-2% by weight), zinc stearate (most preferably employed in the range of 0.5-1.5% by weight).or stearic acid (most preferably employed in the range of 1-3% by weight); hydrogenated vegetable oil (most preferably employed in the range of 1-5% by weight); polyalkylene glycols such as polyethylene glycol (most preferably employed in the range of 1-5% by weight); sodium benzoate (most preferably employed in the range of 2-5% by weight); or talc (most preferably employed in the range of 1-5% by weight).
The xe2x80x9csurfactantxe2x80x9d employed in a composition of the present invention may be one or more compounds which are capable of improving the wetting of the tablets and/or enhancing dissolution. Preferred surfactants are sodium lauryl sulfate (most preferably employed in the range of 0.2-6% by weight), and poly(oxyethylene),poly(oxypropylene) block co-polymers such as poloxamers, especially poloxamer 188 (most preferably employed in the range of 1-6% by weight).
The xe2x80x9ccoloring agentxe2x80x9d (or xe2x80x9ccolorantxe2x80x9d) employed in a composition of the present invention may be one or more compounds which impart a desired color to a tablet prepared from the composition. Addition of a coloring agent may be used, for example, so that tablets of different potencies may be easily distinguished. Preferred coloring agents are ferric oxides, which are universally accepted.
As can be seen from the above, a single compound may perform two or more functions. Calculation of weight percent is preferably on the basis of the primary function of a compound in a given composition. The present compositions preferably consist essentially of, most preferably, consist of the above-described components.
Preferred Composition
Preferred compositions of the present invention contain one or more of the following components in the indicated concentration range (% by weight): irbesartan, 20 to 60 (e.g., 25 to 60), such as 30 to 60, most preferably, 30 to 50, especially about 50%; diuretic, 2 to 20, most preferably 2 to 17, especially 4 to 9%; diluent, I to 70, most preferably 1 to 60, especially 1 to 40%; binder, 5 to 20, most preferably 5 to 15%; disintegrant, 4 to 8, most preferably about 5%; antiadherent, 0.25 to 5.0% (such as 0.25 to 1.5, most preferably 0.7 to 0.8%, for example, when a diuretic is present or 2.5 to 3.0%, for example, when a diuretic is not present); lubricant, 0.5 to 1.5, most preferably about 1%; and surfactant, 1 to 3, most preferably, about 3%.
The following tables recite preferred compositions of the present invention which produce tablets of especially high quality and superior performance. Table A recites preferred compositions containing irbesartan; Table B recites preferred compositions containing irbesartan in combination with a diuretic.
In the above compositions of Table A, the combination of magnesium stearate and silicon dioxide provides a superior lubrication effect while minimizing any decline in tablet dissolution performance; the intragranular:extragranular placement ratio of the disintegrant croscarmellose sodium is superior (e.g., 1:1); and the poloxamer surfactant improves the aqueous granulation of irbesartan (which is hydrophobic), eases the ejection of tablets after compression and accelerates the dissolution of the irbesartan active agent.
The compositions of Tables A and B preferably also contain 0.08 to 0.12% by weight ferric oxide, red and 0.08 to 0.12% by weight ferric oxide, yellow as a colorant.
Methods of Manufacture
Tablets may be prepared from the present compositions by any suitable method for forming tablets. Preferably, tablets are prepared from the present compositions by a wet granulation process. An exemplary such method comprises the following steps:
(a) preparing an intragranular composition by:
(i) mixing the irbesartan, diuretic (for combined tablets), a portion of the diluent (preferably, from about 5 to about 80% by weight of the total diluent), a portion of the disintegrant (preferably, from about 50 to about 80% by weight of the total disintegrant), the binder, and, optionally, a portion of the antiadherent (preferably, from about 50 to about 80% by weight of the total antiadherent), to form a powder blend and, optionally, sizing the blend (e.g., milling the blend to break up aggregates);
(ii) re-mixing the blend;
(iii) granulating the blend with a granulating fluid, preferably water and/or an aqueous solution of the surfactant, to form granules (e.g., using a high shear mixer/granulator);
(iv) drying the granules (e.g., in an oven or, preferably, in a fluid bed dryer); and
(v) sizing the dried granules (e.g., by milling or screening);
(b) preparing a mixture of the sized granules of step (a)(v) with an extragranular composition by:
(i) mixing the remainder of the diluent, the remainder of the disintegrant, the antiadherent or the remainder of the antiadherent, and, optionally, the coloring agent, where one or more of these may be pre-blended, sized (e.g., milled to break up aggregates) and re-mixed prior to this step, with the sized granules from step (a)(v) to form a granule blend; and
(ii) mixing the lubricant with the granule blend; and
(c) compressing the mixture from step (b)(ii) to form tablets (for example, employing a tablet press).
The solid starting materials of the present compositions are preferably screened prior to use. The weight ratio of water (preferably, purified water, USP or water for injection,.USP) to solids employed in step (a)(iii) is preferably within the range of from about 0.25:1 to about 0.6:1.
The tablets may, optionally, be finished or coated such as by methods known in the art.
The tablets prepared from the compositions of the present invention preferably contain (per tablet) from about 25 to about 300 mg of irbesartan, most preferably from about 75 to 300 mg of irbesartan and, for the combined tablets, an additional amount of from about 1 to about 25 mg of diuretic, most preferably from about 6.25 to about 25 mg of hydrochlorothiazide. The total weight of the tablets prepared is preferably from about 50 to about 600 mg. In addition to tablets, the compositions of the present invention may be used to prepare beads, granules for dispersion or capsules, the latter, for example, filled with powder or the aforementioned beads or granules. Methods such as those well known in the art may be used to prepare these dosage forms.
The compositions and tablets of the present invention may be used to treat or prevent disorders such as those described in U.S. Pat. No. 5,270,317, incorporated herein by reference. Such disorders include cardiovascular disorders, for example, hypertension or heart failure, venous insufficiency, as well as glaucoma, diabetic retinopathy, renal insufficiency and various complaints of the central nervous system. The present compositions or tablets are preferably administered orally, in an effective amount, to a mammalian (especially, human) subject to treat or prevent the aforementioned disorders. For human subjects, preferred dosages of from about 75 mg to about 300 mg of irbesartan (alone or in combination with a diuretic) may be administered, for example, 1 to 2 times per day.
The following Examples are provided to illustrate preferred embodiments of the invention, and are not intended to limit the scope of the present claims.